rs202013788

Positions:

• chr2-71600781-C-A
• chr2-71600781-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001130987.2(DYSF):​c.3836C>A​(p.Thr1279Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.374

Genes affected

DYSF (HGNC:3097): (dysferlin) The protein encoded by this gene belongs to the ferlin family and is a skeletal muscle protein found associated with the sarcolemma. It is involved in muscle contraction and contains C2 domains that play a role in calcium-mediated membrane fusion events, suggesting that it may be involved in membrane regeneration and repair. In addition, the protein encoded by this gene binds caveolin-3, a skeletal muscle membrane protein which is important in the formation of caveolae. Specific mutations in this gene have been shown to cause autosomal recessive limb girdle muscular dystrophy type 2B (LGMD2B) as well as Miyoshi myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13260433).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.3836C>A	p.Thr1279Lys	missense_variant	34/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.3782C>A	p.Thr1261Lys	missense_variant	34/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.3836C>A	p.Thr1279Lys	missense_variant	34/56	1	NM_001130987.2	ENSP00000386881	A1
DYSF	ENST00000258104.8	c.3782C>A	p.Thr1261Lys	missense_variant	34/55	1	NM_003494.4	ENSP00000258104	A1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74316

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Qualitative or quantitative defects of dysferlin Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2021

This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 1261 of the DYSF protein (p.Thr1261Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DYSF-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DYSF protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.9
DANN	Benign	0.29
DEOGEN2	Benign	0.21	.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.81	T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.6	.;.;L;.;L;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.97	T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.94	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.044	B;B;B;B;B;B;B;B;B;B;B
Vest4		0.36
MutPred		0.39		.;.;Gain of methylation at T1261 (P = 0.0165);.;Gain of methylation at T1261 (P = 0.0165);.;.;.;.;.;.;
MVP		0.40
MPC		0.19
ClinPred		0.029	T
GERP RS		-4.5
Varity_R		0.056
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs202013788; hg19: chr2-71827911;